Second-placed Milan's hopes of winning the match to pull within three points of Inter with a game in hand will suffer a big blow if Nesta fails to recover from a leg muscle strain that forced him to come off in last weekend's 4-0 win over Siena.
Nesta has frequently been described as Milan's best close season 'acquisition' after returning from a career-threatening back injury to help make up for the loss of retired captain Paolo Maldini this season.
The understanding the former Italy international has developed with Brazilian centre-back Thiago Silva has been fundamental to Milan's strong revival from a shaky start, which included a 4-0 defeat to Inter in the early season fixture.
Milan also have other injury problems, but Nesta's fitness seems to be their biggest concern given his influence and the cover they have in other areas.
"Nesta is much more than just a player," Gennaro Gattuso was quoted as saying by Thursday's La Gazzetta dello Sport.
Brazilian forward Alexandre Pato has failed to shake off a thigh problem, which means David Beckham is likely to continue to deputise on the right of a front three even if Clarence Seedorf regains fitness.
Mathieu Flamini has a knock and Gianluca Zambrotta told reporters on Thursday he will not have recovered from a calf problem in time to play on Sunday.
Inter coach Jose Mourinho is concerned about his midfield, as Thiago Motta and Dejan Stankovic are injury doubts and Sulley Muntari pulled up in training with a thigh problem on Wednesday.
Mourinho joked that the Italian league should postpone the match because of these injuries after Milan managed to get a fixture rescheduled, irritating Inter and adding an extra dimension to the usual heated rivalry ahead of a San Siro derby.
Milan had their Italian Cup quarter-final against Udinese moved to January 27, just a day before Inter face Juventus in the Cup on the same pitch, so they would have a free week before the derby like their city rivals.
AS Roma coach Claudio Ranieri may field new arrival Luca Toni up front alongside fit-again Francesco Totti for the first time in Saturday's visit to his faltering former side Juventus.
Toni, on loan from Bayern Munich, helped in-form Roma go third by scoring twice in Sunday's 3-0 win over Genoa.
Ciro Ferrara, who replaced Ranieri in the Juve dugout just before the end of last season, is under pressure after his side dropped to fifth with last weekend's 1-0 loss at Chievo Verona, their fifth defeat in seven league games.
Ferrara still has a long injury list and Felipe Melo is suspended but the situation eased this week with Italy midfielder Antonio Candreva arriving on loan and Mali international Mohamed Sissoko returning from the African Nations Cup.
One of the end stands of Turin's Stadio Olimpico will be closed after Juve's fans sang racist chants in last week's 3-0 win over Napoli in the Italian Cup.
